Sonic hedgehog, a regulator of CN injury induced apoptosis

描述(申请人提供)：勃起功能障碍(ED)影响52%的40岁至70岁的男性。30-87%的前列腺癌患者经历ED，而29-86%的前列腺癌患者经历ED的PDE5抑制剂无效，这取决于他们的神经损伤状况。在这一人群中，治疗效果的降低使得治疗ED的新的治疗方法变得至关重要。在动物模型和人类ED患者中，阴茎平滑肌细胞凋亡显著增加是常见的。我们认为，切断阴茎核后，阴茎平滑肌中大量的细胞凋亡是导致ED发生的主要因素。如果在前列腺切除后CN再生的同时能够防止细胞凋亡，那么正常勃起功能的恢复将会更快，导致勃起功能障碍的阴茎不可逆的形态变化将被阻止。了解调控阴茎平滑肌细胞凋亡的机制对于开发治疗和预防勃起功能障碍的新的治疗方法至关重要。Sonic Hedgehog(SHH)是阴茎平滑肌的重要调节剂。当阴茎中SHH被抑制时，导致勃起功能障碍的平滑肌细胞凋亡增加12倍。Shh蛋白治疗能抑制CN损伤诱导的细胞凋亡，提示Shh有可能通过抑制血管细胞凋亡来预防ED。这些研究中使用的Affi-Gel微珠技术不适用于人类，因此我们建议将SHH蛋白纳米粒递送到阴茎，并假设通过纳米粒递送SHH将有效抑制CN损伤引起的细胞凋亡诱导。这项新技术有很大的潜力被开发成一种治疗方法，在前列腺癌切除时防止患者的细胞凋亡，因此具有重要的临床意义。SHH本身是如何在阴茎中调节的，以及SHH蛋白减少如何诱导细胞凋亡的机制还知之甚少。可能是神经输入/完整性调节了阴茎中的SHH，因为在两种神经病变模型中，SHH蛋白显著减少，即CN损伤大鼠和BB/WOR糖尿病大鼠。由于SHH蛋白在糖尿病人阴茎中的降低与在大鼠中的观察结果平行，这为SHH蛋白降低如何诱导阴茎细胞凋亡提供了临床意义。我们的结果提示，在CN损伤后，髋外与ptch1竞争SHH结合。因此，我们假设，神经输入的丢失通过ptch1和髋关节依赖的机制减少了阴茎中SHH蛋白的表达，并诱导了阴茎平滑肌中的细胞凋亡。公共卫生相关性：勃起功能障碍(ED)是一种重要的医学状况，目前的治疗方案对糖尿病患者和接受前列腺切除术的前列腺癌患者无效。Sonic Hedgehog(SHH)是一种重要的阴茎平滑肌调节剂，可通过抑制平滑肌细胞凋亡来预防勃起功能障碍。我们建议开发SHH蛋白的纳米颗粒递送作为一种治疗方法，以防止前列腺切除术患者的细胞凋亡。SHH本身如何在阴茎中调节以及SHH蛋白减少如何诱导细胞凋亡的机制还知之甚少，将在本提案中进行深入研究。

DESCRIPTION (provided by applicant): Erectile dysfunction (ED) affects 52% of men between the ages of 40 and 70. 30-87% of prostate cancer patients treated by prostatectomy experience ED and PDE5 inhibitors are ineffective in 29-86% of prostatectomy patients who experience ED, depending on their nerve injury status. The reduced efficacy of treatments in this population makes novel therapeutic approaches to treat ED essential. Significantly increased apoptosis of penile smooth muscle is common in both animal models and human patients with ED. We propose that abundant apoptosis observed in penile smooth muscle when the CN is cut is a major contributing factor to ED development. If apoptosis could be prevented following prostatectomy while the CN regenerates, then resumption of normal erectile function would occur more quickly, and irreversible morphology changes in the penis that cause ED would be prevented. Understanding the mechanisms that regulate smooth muscle apoptosis in the penis is critical for development of new therapeutic approaches for ED treatment and prevention. Sonic hedgehog (SHH) is an essential regulator of penile smooth muscle. When SHH is inhibited in the penis, there is a 12-fold increase in smooth muscle apoptosis that results in ED. SHH protein treatment is able to suppress CN injury induced apoptosis, indicating that SHH has significant potential to be developed as a treatment to prevent ED by suppressing smooth muscle apoptosis. The Affi-Gel bead technology used in these studies is not applicable to humans, so we propose to develop nanoparticle delivery of SHH protein to the penis and hypothesize that SHH delivery via nanoparticles will be effective in suppressing apoptosis induction caused by CN injury. This novel technology has substantial potential to be developed into a therapy to prevent apoptosis in patients at the time of prostatectomy, so has significant clinical relevance. The mechanism of how SHH itself is regulated in the penis and how decreased SHH protein induces apoptosis is poorly understood. It is likely that neural input/integrity regulates SHH in the penis since SHH protein is significantly decreased in two models of neuropathy, the CN injured rat and in the BB/WOR diabetic rat. Since SHH protein is decreased in diabetic human penes in parallel with observations in the rat, this lends clinical significance to how decreased SHH protein can induce apoptosis in the penis. Our results suggest that HIP out competes PTCH1 for SHH binding after CN injury. Thus we hypothesize that loss of neural input decreases SHH protein in the penis and induces apoptosis in penile smooth muscle through a PTCH1 and HIP dependent mechanism. PUBLIC HEALTH RELEVANCE: Erectile dysfunction (ED) is a significant medical condition and current treatment options are ineffective in diabetic patients and in prostate cancer patients treated by prostatectomy. Sonic hedgehog (SHH) is an essential regulator of penile smooth muscle that has significant potential to be developed as a treatment to prevent ED by suppressing smooth muscle apoptosis. We propose to develop nanoparticle delivery of SHH protein as a therapy to prevent apoptosis in patients at the time of prostatectomy. The mechanism of how SHH itself is regulated in the penis and how decreased SHH protein induces apoptosis is poorly understood and will be examined in depth in this proposal.